3-(2-fluorophenyl)-1,2,3-benzotriazin-4-one



United States Patent 3,445,465 3-(Z-FLUOROPHENYL)-1,2,3-BENZO-TRIAZlN-4-ONE Gerhard Satzinger, Gundelfingen, Freiburg, Germany, as-

signor to Warner-Lambert Pharmaceutical Company, Morris Plains, N.J., acorporation of Delaware No Drawing. Continuation-impart of applicationSer. No. 432,012, Feb. 11, 1965. This application Sept. 11, 1967, Ser.No. 666,955 7 Int. Cl. C07d 55/08 US. Cl. 260-248 1 Claim ABSTRACT OFTHE DISCLOSURE This invention relates to 3-(2-fluorophenyl)-1,2,3-benzotriazin-4-one of the formula:

F f I /N o H 0 which is useful as an anoretic agent in the mammalianbody.

Cross reference This application is a continuation-in-part ofapplication Ser. No. 432,012 filed on Feb. 11, 1965, now abandoned.

Summary of the invention This invention relates to a new and novel3-substituted 1,2,3-benzotriazin-4-one. In particular, the presentinvention relates to 3-(2-fluorophenyl)-1,2,3-benzotriazin-4 one havingthe formula:

and to pharmaceutical compositions containing it.

Description of the preferred embodiments The present invention relatesto 3-(2-fluorophenyl)- 1,2,3-benzotriazin-4-one having the formula:

N F N I ll:

to pharmaceutical compositions containing it, and to methods ofproducing anorexia in the mammalian body. This compound exhibits unusualpharmacological properties. As will be discussed in more detail later,this systemically extremely well-tolerated compound is distinguished byits outstanding anoretic-antisecretory activity in the mammalian body.Since this substance also has a sedative effect on the central nervoussystem, it compares very favorably with all known anoretic agents, whichare generally recognized as producing, in addition to their anoreticeffect, a most undesirable stimulation of the central nervous system.

The novel compounds of this invention can be obtained by an adaptationof the process disclosed in the following publications: J. Org. Chem.,9, 55 (1944); Compt. rend., 243, 2094 (1956), J. Org. Chem., 26, 613(1961);

3,445,465 Patented May 20, 1969 ice 27, 1383 (1962); J. pract. Chem. (2)(1963), according to the following reaction scheme:

In the above reaction scheme, isatoic anhydride (I) is reacted witho-fluoraniline (II) at about C. to about 200 C. Since it is desirablethat the primary amine serve both as a reactant and as the solvent, anexcess, such as at least 3 mols (per mole of isatoic anhydride) of theprimary amine is desirably included in the reaction mixture. Greateramounts of the primary amine may also be used if desired. By thisprocedure, very weakly basic or hindered amines can still be caused toreact with satisfactory yields. If an excess of ofluoraniline is notused, autocondensation products of isatoic acid anhydride will beobtained as byproducts.

The substituted anthranilamide compound (III) is then diazotized at atemperature of about 0-5 C. with a mixture of an alkali metal nitrite,such as sodium nitrite, and about equal parts of 3 N H 80 and a loweralkanol such as methanol, ethanol, n-propanol, and the like, preferably,n-propanol. The reaction product of the diazotization IV is cyclizedwithout prior isolation by heating the resulting mixture to atemperature of about 20 C. to about 60 C. A temperature in the rangefrom 20 C. to 30 C. is preferred. The compound 3-(Z-fluorophenyl)-1,2,3-benzotriazin-4-one (V) is recovered by standardtechniques.

In order to facilitate comprehension of the present invention, thefollowing example is given. All temperatures are in degrees centigrade.

EXAMPLE 1 3-(2-fiuorophenyl) -1,2,3 benzotria2in-4-one A suspension of163 gms. (1 mol) of isatoic anhydride in 555 gms. (5 mols) ofo-fluoroaniline is heated at 180 with agitation until CO evolution hasceased. Excess o-fiuoraniline is distilled off in a vacuum and theresidue is suspended in a mixture of 400 ml. ice cold 3 N H 80 and 400ml. n-propanol and is slowly treated at 0-5 with a solution of 25 mgs.of NaNO in 65 ml. water. After agitation for another half hour at thistemperature, the system is diluted to double volume with water and thenagitation continued at 30 for two additional hours.

Thereafter, the prepared product is filtered with suction and thoroughlywashed with water. 28 gms. of 3-(2fluorophenyl)-1,2,3-benzotriazin-4-one is obtained afterrecrystallization from ethanol and benzene and is found to have amelting point of 142 C.

The pharmacological Properties of 3-(2-fiuorophenyl)-1,2,3-benzotriazin-4-one are as follows:

Toxicity.The toxicity of 3-(2-fiuorophenyl)-1,2,3- benzotriazin-4-one,prepared in accordance with Example I, was determined in the followingmanner:

Increasing doses of this compound were administered intragastrically onan empty stomach to male mice of a weight between 17 and 21 gms. bymeans of a stomach tube. The doses were increased in a logarithmicmanner. The mice so treated were observed for 7 days. Administration of5000 mg./ kg. of the compound 3-(2-fluorophenyl)-1,2,3-benzotriazin-4-one prepared according to Example I resulted in thedeath of less than half ofthe mice. Thus, the LD of3-(2-fiuorophenyl)-1,2,3-benzotriazin-4-one in mice exceeds 5000 mg./kg.

Anticonvulsant activity.The anticonvulsant activity of a substance maybe used as a criterion of its sedative action on the central nervoussystem. The compound of the instant invention, 3 (2 fluorophenyl) 1,2,3benzotriazin-4-one, has a distinct anticonvulsant activity of the orderof the commercially available anticonvulsants, e.g., trimethadione (Tridione). To determine the anticonvulsant activity of3-(2-fluor0phenyl)-1,2,3-benzotriazin-4-one, a dose of 200 mg./kg. ofthis substance was administered to mice. A similar group of mice wasgiven 300 mg./ kg. of Tridione while another group of mice was given aplacebo composition. The test animals were male mice of 18-22 g. ofweight. Each of the three groups of mice were then challenged with a 120mg./kg. dosage of pentetrazol, administered subcutaneously.Anticonvulsant activity was determined by evaluating the extensor muscleconvulsions in the mice. The results are tabulated in the followingtable which show that all the mice given pentetrazol following previousdoses of trimethadione exhibited external muscle convulsions whereas themice given 3-(2-fiuorophenyl)-1,2,3-benzotriazin-4-one followed bypentetrazol were free of extensor motor convulsions. This establishesthat 3-(2-fluorophenyD-1,2,3-benzotriazin-4-one does, quiteunexpectedly, possess central nervous system depressant activity.

3 (2 fiuorophenyl) 1,2,3 benzotriazin 4 one has marked anoretic activitywithout central nervous system stimulant activity. It also has anexceptionally low toxicity.

It is therefore useful as an anoretic agent in the mammalian body. Forexample, it is useful in treating obesity in dogs, cats, and humanbeings.

In use, this compound can be formulated with conventional pharmaceuticalcarriers to form such typical oral or rectal dosage units as tablets,capsules, solutions, suspensions, suppositories and the like. From about300 mg. to about 600 mg. of this compound can be administered daily tothe human adult in divided doses; smaller dosages can, of course, beemployed for the young or debilitated elderly patients.

EXAMPLE II Tablets containing the compound of this invention areformulated as follows:

Grams, 1000 tablets 3-(2-fiuorophenyl) -1 ,2,3-benzotriazin-4-onePolyvinylpyrrolidone 3 Isopropanol 30 Corn starch 18 Avicel 18 Magnesiumstearate 1 The 3-(2-fluorophenyl)-1,2,3-benzotriazin-4-one is granulatedwith a 10% solution of polyvinylpyrrolidone in isopropanol. Corn starch,avicel and magnesium stearate are added to the dried granulation and themixture is compressed into tablets.

It is understood that the foregoing detailed description is given merelyby way of illustration and that many variations may be made thereinwithout departing from the spirit and scope of this invention.

What is claimed is:

1. 3-(2-fiuorophenyl) 1,2,3-benzotriazin-4-one of the formula:

HENRY R. JILES, Primary Examiner.

JOHN M. FORD, Assistant Examiner.

US. Cl. X.R.

